Abstract Drug addiction is a chronic brain disease characterized by compulsive use of drugs despite negative consequences. Risk of relapse remains elevated even after long periods of abstinence due to drug-associated cues that provoke drug craving and seeking. Currently, there are no effective pharmacotherapeutic interventions for addiction to stimulants, such as cocaine, highlighting the urgent need for further understanding of the neurobiology of addiction. In an animal addiction model of persistent relapse vulnerability, extended- access cocaine self-administration leads to an abstinent-dependent intensification of cue-induced cocaine craving, a phenomenon that has also been observed in human addicts. While the reward circuitry of the brain is known to play an important role in the drug-dependent plasticity that underlies the addiction disease, the hippocampus (HPC), a crucial member of the circuitry, has not been examined in the progression and maintenance of intensified cue-induced cocaine seeking. Our objective is to investigate the role of activin signaling in the HPC in cue-induced cocaine seeking following both acute and prolonged abstinence. Activin signaling was recently implicated in neuronal and behavioral plasticity following exposure to drugs of abuse, indicating that this pathway is a substrate mediating the long-term addicted disease state. Cellular processes in the HPC following cocaine exposure and prolonged abstinence have not been well studied. Therefore, deeper exploration of cocaine-induced plasticity in the HPC that may underlie relapse behaviors is desperately needed. The overarching focus of this proposal is to detail the molecular mechanisms of cocaine-induced cellular and behavioral plasticity in the HPC following abstinence to cocaine self-administration. To this end, we have proposed two Specific Aims. Following cocaine self-administration and subsequent abstinence, there is an increase in hippocampal activin A following re-exposure to cues previously paired with availability of cocaine during prolonged, but not acute, abstinence. We propose that activin signaling in the HPC is essential for the expression of intensified cue-induced cocaine-seeking behavior (Aim I). Furthermore, we propose that intensification of cue-induced seeking is mediated through activation of the understudied, non-conical activin signaling cascade in the HPC (Aim II). This application presents an opportunity to determine, for the first time, a causal mechanism of activin signaling in the hippocampus in the underlying cellular and behavioral plasticity induced by abstinence following cocaine self-administration. The corresponding research plan will elucidate a novel mechanism by which chronic cocaine exposure induces long-term adaptations in the HPC and will provide new direction for the development of novel therapies for cocaine addiction.